The ultimate goal of this project is to identify the gene that is mutated in Aicardi syndrome, a rare neurodevelopment disorder that affects almost exclusively females and is associated with mental retardation. It is thought to be caused by de novo X-linked dominant heterozygous mutations. Affected girls present with a typical triad of agenesis of the corpus callosum, severe seizures (infantile spasms) and chorioretinal lacunae. Other defects, including abnormalities of neuronal migration, optic nerve and other organ systems are often present. This suggests that the gene mutated in Aicardi syndrome has important complex functions in normal development. There is more variability in the phenotype than was initially ascertained, which may in part result from differences in X chromosome inactivation (XCI) patterns between patients. In addition, a small subset of patients with the most complex phenotype may have a genomic deletion or duplication that affects the function of more than one gene. Because all cases of Aicardi syndrome are sporadic, genetic linkage to map the locus that harbors the mutated gene is not possible. For this research project we propose three specific aims to pursue other novel strategies to find the Aicardi syndrome gene. In specific aim 1, we will characterize the phenotype in more detail and study XCI patterns on a large number of patient DNAs to provide further support for the X-linked inheritance of the condition. In specific aim 2, we will use comparative genomic hybridization on genomic DNA micro arrays to screen for micro deletions or duplications in DNA from patients. In the third specific aim, we will perform mutation analysis of candidate genes on the X chromosome that will be selected based on their known or putative function and their expression pattern. To select these genes, we will also take into account the molecular pathways that are disrupted in conditions with similar phenotypes and the pathways that orchestrate the development of the organ systems most affected in Aicardi syndrome. As for other rare neurodevelopment disorders, finding the Aicardi syndrome gene will not only benefit diagnosis and treatment of this disorder, it will also increase knowledge on molecular pathways that guide development of the brain, eye and other affected organ systems. Understanding these biological processes will benefit discovery, diagnosis and treatment of many developmental disorders. This will improve the health of children. [unreadable] [unreadable] [unreadable]